Haemophilus ducreyi is the etiologic agent of chancroid, a genital ulcer disease transmitted by sexual contact. See, e.g. Albritton, W. L., Microbiol Rev. 53:377–89 (1989); Trees, D. L., and S. A. Morse, Clin Microbiol Rev. 8, 357–375 (1995). Chancroid has gained importance recently because it has been implicated as an independent risk factor for the heterosexual transmission of HIV in Africa. See Albritton, supra Trees, supra: R. M. Greenblattet et al., AIDS 2, 47–50 (1988); Jessamine, P. G., and A. R. Ronald, Med Clin North Am. 74, 1417–31 (1990); Plummer, F. A. et al., J Infect Dis. 161, 810–1 (1990); D. L., and S. A. Morse, Clin. Microbiol Rev. 8, 357–375 (1995): Wasserheit, J. N., Sex Trans Dis. 19, 61–77 (1991).
Serum resistance has been shown in numerous bacterial systems to be critical for the survival of invading bacterial and the establishment of disease, since mutations which result in the loss of serum resistance renders several bacterial pathogens avirulent. See. e.g., Blaser, M. J., American Journal of the Medical Sciences. 306, 325–9 (1993); Corbeil, L. B., Canadian Journal of Veterinary Research. 54,S57–62 (1990), Mobley, H. L. et al., Kidney International—Supplement. 47, S129–36 (1994); Rice, P. A., Clinical Microbiology Review. 2, S112–7 (1989); and Stull, T. L., and J. J. LiPuma, Medical Clinics of North America. 75, 287–9 (1991). In most systems, the serum resistance phenotype is the product of multiple genes. H. ducreyi is resistant to high levels of normal human serum (NHS; up to 50%). Early studies on H. ducreyi serum resistance by Odumeru and colleagues concluded that truncation of LOS in several strains was associated with avirulence and loss of serum resistance (see Odumeru, J. A. et al., Infect. Immun. 43, 607–611 (1984); Odumeru, J. A. et al., Infect. Immun. 50, 495–9 (1985); Odumeru, J. A. et al., J Med Microbiol. 23, 155–62 (1987)), whereas a recent study came to the opposite conclusion. See Hiltke, T. J. et al., Microb Path. 26,93–102 (1999)
Originally described as a cell spreading factor, vitronectin is now recognized as a multifunctional regulatory adhesive glycoprotein involved in a variety of extracellular processes such as the attachment and spreading of normal and neoplastic cells, as well as the function of the complement and coagulation pathways. Integrins are transmembrane αβ heterodimer receptors expressed on a wide variety of cells which are involved in extracellular matrix interactions. The ligands for several of the integrins are adhesive extracellular matrix (ECM) proteins such as fibronectin, vitronectin, collagens and laminin.
Proteins or fragments thereof that are able to interfere with vitronectin binding to various integrins and to block integrin-mediated cell attachment to extracellular matrix proteins are useful in preventing the attachment of the bacteria to the host organism, and thus infection of the host.
The ability to use a protein or antibody that interferes with vitronectin binding in a vaccine against H. ducreyi is desirable. These kinds of proteins are believed to be highly conserved among strains of a particular type of bacteria in that they are the protein molecules that mediate attachment by bonding bacteria to host cells, the initial step in the infection process. A vaccine against H. ducreyi comprising a protein or antibody that would interfere with vitronectin binding would be effective against a broad array of types and strains of H. ducreyi. The use of such a vaccine may prevent adherence of the bacteria to the tissue of the host animal. In that adherence is one of the initial step in H. ducreyi infection, accordingly, preventing or limiting the infection at this point would be advantageous.
In view of the foregoing, it would be desirable to determine the mechanism of serum resistance in H. ducreyi. Additionally, the development of an effective vaccine against H. ducreyi would be advantageous.